5,6-dihydro and 1,2,3,4,5,6-hexahydro-8-alkoxy - 9h - indolo - (2,3 - c)isoquino(1,2 - f)(1,2) azaphosphorine 8-oxides and process for their production



United States Patent ffice 3,452,024 Patented June 24, 1969 5,6-DIHYDRO AND 1,2,3,4,5,6-HEXAHYDRO-8-ALK- OXY 9H INDOLO [2,3 c]ISOQUINO[1,2 f][l,2] AZAPHOSPHORINE S-OXIDES AND PROCESS FOR THEIR PRODUCTION John Shavel, Jr., Mendham, and Glenn Curtis Morrison,

Dover, N..I., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Filed July 28, I966, Ser. No. 568,413

Int. Cl. C07d 105/02, 27/56; A6lk 27/00 US. Cl. 260-288 6 Claims ABSTRACT OF THE DISCLOSURE Compounds of the following formulae are being claimed:

N N P wherein R and R each represents lower alkyl. These compounds are used as central nervous system stimulants.

and

The present invention relates to new and novel 5,6- dihydro and l,2,3,4,5,6-hexahydro-8-alkoxy-9H-indolo- [2,3-c]isoquino[1,2-f][1,2]azaphosphorine 8-oxides having the formulae:

and

wherein R and R each represents lower alkyl such as methyl, ethyl, propyl, butyl, isobutyl and the like. The

2 symbols R and R have the same meaning as defined.

The compounds of this invention have the following numbering system:

The compounds of this invention are useful as central nervous system stimulants. In order to use these compounds to produce the desired central nervous system stimulation, they are given at a dosage of about 1 to mg. to an animal, orally or parenterally. The dosage regimen may be adjusted according to the requirements of the animal.

Compound I of this invention is an amide of the formula:

o HN N H III whereas the compound of this invention of the Formula prepared by reacting II above is prepared by treating an amide of the formula HN \J 8 -ethoxy-5 ,6 -dihydro-2, 3-dimethoxy-9H-indolo [2, 3 -c] isoquino-[ 1,2-f] [1,2] azaphosphorine 8-oxide A solution of 15.0 g. of N-(3,4-dimethoxyphenethyl) indole-3-acetamide in 48 ml. of phosphorous. oxychloride is refluxed for hr. The reaction mixture is stripped in vacuo on the steam bath and the residue is treated with 100 ml. of ethanol giving a solid, M.P. 300. A solution of the solid in 700 ml. of ethanol is refluxed for 2.5 hr. and then concentrated to 100 ml. On standing there is deposited the above compound as a crystalline solid, M.P. 285.5-286.5.

Analysis.Calcd. for C H N O P: C, 64.38; H, 6.65; N, 6.83; P, 7.55. Found: C, 64.36; H, 5.88; N, 6.71; P, 7.82.

EXAMPLE 2 8-ethoxy-1,2,3,4,5,6-hexahydro-9H-indolo [2,3 -c] isoquino- [1,2-f] [1,21azaphosphorine S-oxide O OCHzCHa A solution of 50 g. of N-(cyclohexenylethyl)indole 3-acetamide in 175 ml. of phosphorous oxychloride is refluxed for 20 hr. The reaction mixture is stripped in vacuo on the steam bath. The residue is poured intowith 300 ml. of ethanol and the mixture refluxed for 1 hr. On standing the solution deposits the above compound as a crystalline solid, M.P. 254-255 Analysis.--Calcd. for C H N O P: C, 67.78; H, 6.54; N, 7.90; P, 8.74. Found: C, 67.79; H, 6.46; N, 7.73; P, 8.61.

It is understood that the foregoing detailed description is given merely by way of illustration.

Having described our invention, what we desire to secure by Letters Patent is:

1. A compound of the formula:

in which R represents lower alkyl. 2. A compound of the formula:

wherein R and R each represents lower alkyl.

3. 8-ethoxy-5,6-dihydro 2,3 dimethoxy 9H indolo [2,3-c]-isoquino[1,2-f] [1,2] azaphosphorine 8-oxide.

4. 8-ethoxy-1,2,3,4,5,6-hexahydro 9H indolo {2,3-c]- is0quino[1,2f] [1,2] azaphosphorine 8-oxide.

5. Process for the production of the compound of claim 1 which comprises treating a compound of the Formula III with phosphorous oxychloride at a temperature of from about C. to about C. to obtain a reaction product, treating said reaction product with a lower aliphatic alcohol.

6. Process for the production of the compound of claim 2 which comprises treating a compound of the Formula IV with phosphorous oxychloride at a temperature of from about 60 C. to about 110 C. to obtain a reaction product, treating said reaction product with a lower aliphatic alcohol.

References Cited UNITED STATES PATENTS 3,291,800 12/1966 Shavel et al. 260-288 ALEX MAZEL, Primary Examiner.

A. M. TIGHE, Assistant Examiner.

US. Cl. X.R. 260-999 

